Our specific aim is to develop strategies for introducing catalytic activity into the combining sites of immunoglobins. Because antibodies can be elicited against most biologically active macromolecules (proteins, nucleic acids and sugars) as well as small synthetic molecules, this approach may enable us to tailor- make semisynthetic molecules, this approach may enable us to tailor-make semisynthetic catalysts with enzyme-like specificities. We are purusing three strategies for introducing catalytic activity into antibody combining sites: (1) transition state stabilization by antibodies, (2) orientational catalysis by antibodies, and (3) site specific chemical modification of antibody binding sites with nucleophiles and cofactors. Antibodies will be elicited against tetrahedral phosphonates and planar bipyridyls as transition state analogues for hydrolysis of the corresponding esters and racemization of bridged-2,2'-bipyridyls, respectively. Antibodies will also be elicited against a cyclic seven-membered ring phosphonate as a transition state analogue for transesterification of an acyclic 6-hydroxy-ester. In addition, antibodies elicited to peptides and L-amino acids will be affinity labeled with thiols and pyridoxamine to afford catalysts for hydrolytic and transamination reactions, respectively. If successful, this work will be a first step in defining those elements necessary for the design and synthesis of catalytic antibodies with defined binding specificities.